The objectives of this proposal are to define the mechanisms of the secretion of lithogenic bile which underlie the increased incidence of cholesterol gallstones in women, especially during the child-bearing age and among those taking contraceptive steroids; to determine the effect of pregnancy, the normal ovulatory cycle and contraceptive steroids on biliary lipid composition, bile acid kinetics, cholesterol secretion and gallbladder function and to relate these effects to changes in naturally occuring female sex hormones; and to seek means of restoring biliary lipid composition to normal and reducing cholesterol cholelithiasis in the above group of patients. Mechanisms of estrogen effects will be studied by: 1) in vitro measurements of hepatic lipid composition and 2) the activity of several hepatic microsomal enzymes, including 7 alpha hydroxylase, cholesterol acyl CoA transferase and cholesterol esterase. These measurements will be made in liver biopsy material from women at different ages, women taking contraceptive steroids and suitable controls. Biliary lipid composition and secretion, bile acid kinetics and gallbladder function will be measured in pregnant women, women during the normal ovulatory cycle, women receiving contraceptive steroids and in appropriate control groups. Bile-rich duodenal fluid will be used. For the kinetic studies, bile acids will be labeled with either the stable isotope, 13C or the radioactive isotope, 14C, depending upon the study group. Appropriate serum female sex hormone concentrations will be determined at the time of study and will be correlated with changes in biliary lipids and bile acid kinetics, etc. The capacity of phenobarbital, salicylates and possibly other agents to modify the estrogen effects will be tested in animals.